Quantitative Functional Assessment of Ischemic Patients by Cardiopulmonary Exercise and Recovery Indices

Exercise stress testing is commonly used for assessing the presence and severity of coronary ischemia including heart rate (HR) and blood pressure (BP) responses as well as exertional symptoms estimation (Vivekananthan et al., 2000). Cardiopulmonary exercise test (CPET) indices, obtained by direct measurement of exercise respiratory gas exchange, may provide additional important clinical information for further and more quantitative evaluation of the ischemic response. Among these indices are the ventilatory anaerobic threshold (VAT), oxygen consumption (VO2) and the oxygen pulse (O2-P) measured during exercise. These indices mainly reflect cardiac problems (Milani et al., 1995, 2006). However, recovery cardiopulmonary indices have been found to be an important tool for assessing the overall exercise capacity in patients with chronic heart failure (CHF). These indices differ significantly from healthy subjects. The kinetics of post exercise VO2 has been demonstrated to be delayed in relation to the severity of the disease and to be closely related to exercise capacity (Koike et al., 1998). Patients with severe CHF or dilated cardiomyopathy, demonstrated a prolonged recovery period to the baseline levels of VO2 (Pavia et al., 1999; De Groot et al., 1999). Similar results were found in patients with mitral stenosis (Lim et al., 1998). This chapter is based on our five studies, and concerns a quantitative functional assessment of ischemic response in patients with documented coronary artery disease (CAD). The ischemic response was tested using various classic and novel cardiopulmonary indices. The first study demonstrates four O2-P curve variables, achieved during exercise, which correlate well with different degrees of ischemic response. In the second study, the functional results following percutaneous transluminal coronary angioplasty (PTCA) were assessed in chronic CAD patients. In the third study there is a similar assessment of the effect of controlled exercise training in chronic CAD patients. In the fourth study the means by which ischemia can be improved, as a result of regular exercise training is explained. The most recent study deals with recovery indices of VO2 kinetics and their contribution to quantitatively assessing varying degrees of CAD.


Introduction
Exercise stress testing is commonly used for assessing the presence and severity of coronary ischemia including heart rate (HR) and blood pressure (BP) responses as well as exertional symptoms estimation (Vivekananthan et al., 2000).Cardiopulmonary exercise test (CPET) indices, obtained by direct measurement of exercise respiratory gas exchange, may provide additional important clinical information for further and more quantitative evaluation of the ischemic response.Among these indices are the ventilatory anaerobic threshold (VAT), oxygen consumption (VO 2 ) and the oxygen pulse (O 2 -P) measured during exercise.These indices mainly reflect cardiac problems (Milani et al., 1995(Milani et al., , 2006)).However, recovery cardiopulmonary indices have been found to be an important tool for assessing the overall exercise capacity in patients with chronic heart failure (CHF).These indices differ significantly from healthy subjects.The kinetics of post exercise VO 2 has been demonstrated to be delayed in relation to the severity of the disease and to be closely related to exercise capacity (Koike et al., 1998).Patients with severe CHF or dilated cardiomyopathy, demonstrated a prolonged recovery period to the baseline levels of VO 2 (Pavia et al., 1999;De Groot et al., 1999).Similar results were found in patients with mitral stenosis (Lim et al., 1998).This chapter is based on our five studies, and concerns a quantitative functional assessment of ischemic response in patients with documented coronary artery disease (CAD).The ischemic response was tested using various classic and novel cardiopulmonary indices.The first study demonstrates four O 2 -P curve variables, achieved during exercise, which correlate well with different degrees of ischemic response.In the second study, the functional results following percutaneous transluminal coronary angioplasty (PTCA) were assessed in chronic CAD patients.In the third study there is a similar assessment of the effect of controlled exercise training in chronic CAD patients.In the fourth study the means by which ischemia can be improved, as a result of regular exercise training is explained.The most recent study deals with recovery indices of VO 2 kinetics and their contribution to quantitatively assessing varying degrees of CAD.
Quantitative Functional Assessment of Ischemic Patients by Cardiopulmonary Exercise and Recovery Indices 61

CPET
An upright symptom-limited test was performed on an electronically-braked cycle ergometer (Ergoline-800).After two minutes of free pedaling, exercise was initiated at 20W followed by increased stepwise of 10-20W every minute until a predefined end-point was reached (i.e., symptoms, volitional fatigue or attainment of target HR).Cardiopulmonary data were collected by an on-line metabolic chart (CPX Medical Graphics, Minn., USA).Patients breathed through a low-resistance, two-way valve (Hans-Rudolph, Mo., USA) connected to the expiratory limb.The breath-by-breath signals were integrated by a computer to yield 30-second averages of HR, minute ventilation (Ve), VO 2 , carbon dioxide output (VCO 2 ) and O 2 -P (=VO 2 /HR).Peak-VO 2 and peak-O 2 -P were related to normal predicted values (Wasserman et al., 1987).VAT was defined as the point at which the ventilatory equivalent of oxygen (Ve/VO 2 ) increases in the absence of such an increase of ventilatory equivalent of carbon dioxide (Ve/VCO 2 ); or as described for the V-slope method, which uses regression analysis to present the inflection point on a plot of VCO 2 vs. VO 2 (Beaver et al., 1986).BP was measured with a cuff sphygmomanometer at the test beginning, and at least twice during exercise and peak exercise.12-lead ECGs were recorded at each one-minute interval throughout the test.The O 2 -P curve appearance was scored on a 10-point scale as follows: Type A, a normal curve (10 points); Type B, a normal ascending curve with relatively low values, not reaching the predicted value at peak exercise (8 points); Type C, an ascending curve reaching a low peak, then flattening through the remainder of exercise on a lower level than the predicted one (5 points), and type D, an ascending curve which may reach the predicted level briefly, then decreases towards the end of the exercise (3 points).These four curves are shown in Figure 1.The hypothesis was, as mentioned above, that type B correlates with mild to moderate ischemic response, curve D correlates with significant ischemia while curve C tends to correlate with LV dysfunction, since these curves reflect the SV dynamics during exercise.

Results
The peak-HR achieved was similar for both tests in all four groups.Since the supine MUGA was the first test done, in which patients usually achieve a lower sub-maximal HR, the CPET was limited to this peak-HR as well.A significant relationship between the MUGA grouping according to exercise response vs. the O 2 -P-curve scoring were demonstrated (Table 1; p<0.001).Figure 2

Conclusions
The present study demonstrates the physiological meaning of the O 2 -P curve scoring which showed a significant correlation with the MUGA response during exercise.Thus, the exercise O 2 -P-C and its scoring, which reflect the SV response during exercise, may serve as a good noninvasive, physiologically-based, parameter for quantitative assessment of ischemic patients and to distinguish between good or impaired LV function.This parameter was used in some of the following studies presented herein, among other indices, for further quantitative evaluation of ischemic patients.

Quantitative assessment of functional results after percutaneous transluminal coronary angioplasty by cardiopulmonary exercise indices
PTCA offers a means of improving the angiographic appearance of coronary arterial stenosis.Although a functional change is expected, owing to the augmented capacity of the dilated coronary artery to deliver blood to the previously ischemic myocardium, restenosis of the dilated vessel may occur.Thus, a recurrence of angina pectoris after successful PTCA is of major concern for both the patient and the clinician.Exercise stress testing has become a valuable clinical tool to assess myocardial efficacy and patient's prognosis following PTCA (Kent et al., 1982).As a result, traditional modalities are used before and after the PTCA procedure, including bicycle ergometer or treadmill exercise test, sequential isotopes myocardial perfusion or stress echocardiography (Fioretti et al., 1992), to assess persistence (dilated) or recurrence (stenosis) of the ischemic response.The success of PTCA may be manifested in global and regional cardiovascular function indices like reduced chest pain, increased ejection fraction, reduced abnormal ST segment morphology as well as improved wall motion and perfusion defects.Bengston et al., 1990 reported that since 20% of patients with restenosis following PTCA had neither recurrent angina nor exercise-induced ischemia, then regular exercise testing should be supplemented with more definite indices.This study was designed to investigate the potential importance of the CPET indices, such as VO 2 , VAT, O 2 -P and its curve appearance, on PTCA follow-up, while assessing the functional results of this procedure.

Methods
29 patients, candidates for PTCA, 26 men and 3 women aged 41-78 years (mean 63.24+/-9) participated.All patients demonstrated good LV function by echo-Doppler tests, although 2 patients had suffered a recent non-Q-wave anterior wall myocardial infarction.All patients underwent a coronary angiography for further evaluation of ischemic heart disease (IHD) before the first CPET.The coronary angiography results are summarized in Table 2.The first CPET was performed within 1-2 weeks before PTCA and the second CPET within 2-4 weeks following PTCA.The same medication regimen was used on both tests, while stopping medications such as beta-blockers, calcium channel blockers and digitalis 24h before each test began.It was intended that similar peak-HRs would be achieved for each individual in both tests.The PTCA results are summarized in Table 3.

CPET protocol
The CPET protocol was performed as described in paragraph 2.1.2.Prior to PTCA, the CPET end-point of the patients was the appearance of angina or significant ST-segment depression, fatigue or target HR.After the PTCA, the CPET was terminated at a similar peak-HR as in the first test, even in the absence of the above pre-PTCA end-points, in order to compare the CPET indices under similar conditions.

PTCA
PTCA was performed within 1-2 weeks after the first CPET if the coronary lesions showed a stenosis of > 70% diameter and were responsible for myocardial ischemia.Successful PTCA was defined as a reduction in stenosis to < 50%     In patients 1 and 2, PTCA was unsuccessful.

Conclusions
After successful PTCA, patients generally showed improvement or absence of perfusion defects and thus achieved higher levels of exercise.The major findings of the present study, as summarized in tables 4 & 5, support this observation: 1) There was a significant functional aerobic improvement following a successful PTCA, as demonstrated by the CPET indices 2-4 weeks after the procedure and 2) This functional improvement occurred with similar peak-HRs in both CPETs, inferring that an increase in O 2 -P is responsible, since VO 2 = HR x O 2 -P.It is concluded that CPET carried out following PTCA is an effective, shortterm, noninvasive method for quantitative functional assessment of the PTCA results.
Further studies are required to determine the long-term effects and prognostic-predicting value for restenosis or for acute coronary events.

Quantitative assessment of functional results following a controlled exercise training program in CAD patients by cardiopulmonary exercise indices
Aerobic exercise training is widely used in patients with CAD, with and without LV dysfunction.It is intended to improve physiological fitness, exercise threshold and anginal symptoms.As a result of exercise training, the maximal VO 2 may increase by 10-30% or more (Clausen & Trap-Jenaen, 1970;Redwood et al., 1972;& Sullivan et al., 1988a).However, not all patients experience improved exercise tolerance and for some there is a negative impact (O'Callaghan et al., 1984;Froelicher et al., 1984;& Grodzinski et al., 1987).One of the most challenging aspects of designing exercise programs for patients with CAD is the prescription of appropriate exercise intensity.It must be effective (not too low) yet not too intense as to be a cardiovascular risk (American College of Sports Medicine, 1990;Kohl et al., 1992).It has been shown that the HR at the VAT level is an optimal target HR for exercise (Gordon & Scott, 1995).This study evaluated the effect of an exercise program, prescribed on the basis of HR at the VAT, in patients with varying degrees of CAD, with good or impaired LV function, by CPET indices.

Methods
Over a 36-month period, 52 male patients, aged 38-75 years, with CAD, completed a 6-9 month supervised, telemetry-monitored, exercise training program.In all patients the CAD was chronic, without any recent coronary events.LV function (expressed by LVEF) was determined by a resting MUGA test.Good LV function was defined when LVEF>45% (32 patients), and LV dysfunction, when LVEF<35% (20 patients).The patients were divided into four groups on the basis of a coronary angiogram and the MUGA test.Groups 1-3 included those with a good LV function as follows: Group 1, 10 patients with single-vessel disease (excluding proximal LAD coronary artery obstruction); Group 2, 12 patients with two-vessel disease, and Group 3, 10 patients with 3-vessel disease.Group 4 included 20 patients with LV dysfunction.The CAD extent was determined by the number of vessels with >50% occlusion.All participants underwent a CPET before and after the exercise training program.The CPET protocol was as described above (paragraph 2.1.2) using the modified Balke treadmill protocol (Froelicher et al., 1974) instead of the bicycle.

Exercise training protocol
All participants completed the exercise program.Each participant was assigned two to three, 30-to 40-min sessions a week of continuous treadmill and bicycle exercise.The training HR was maintained at the VAT level as calculated from the CPET data.Each session was preceded and followed by warm-up and cool-down periods.During exercise, the patients were electrocardiographically monitored by single-lead telemetry (Nihon-Kohden; Life Scope 6).

Results
The variables at baseline and for the four groups are summarized in Table 6.There were no significant differences concerning age or LVEF among groups 1-3.Although the HR for group 3 (three-vessel disease) was lower than in the other groups, it was still relative to the VAT level.The CPET indices before and after the exercise program are summarized in

Conclusions
A 6-9 month exercise training program, determined by HR at the VAT, significantly improves the overall circulatory and cardiac function, as assessed by CPET indices, in CAD patients with one-or two-vessel disease as well as in patients with LV dysfunction, most probably by a peripheral circulatory mechanism in the latter ones.Such improvements were not achieved in patients with three-vessel disease and may be explained by the limitation of significant ischemia which occurred even at this relatively low intensity of exercise.Once again, the CPET was shown to be a sensitive and effective tool for quantitative assessment of exercise training results in CAD patients, in contrast to the routine exercise test variables.It appears, as the PTCA results also demonstrated, that patients with one-or two-vessel disease benefit from an exercise program.This leads us to the next study in which the functional cardiopulmonary indices are evaluated and compared in trained versus untrained CAD patients seeking further explanation of the beneficial effects of exercise for chronic CAD patients.

Quantitative functional assessment and comparison of trained versus untrained CAD patients by combined CPET and 99mTC-Sestamibi myocardial imaging
Several studies, amongst many, have confirmed the overall benefit of exercise training in reducing the risk of CAD (Sesso et al., 2000;Blair et al., 1993).Additional studies have shown specific benefits of exercise training in CAD patients: Improved endothelial function with CHF (Hambrecht et al., 1998) or without CHF (Walther et al., 2004;Hambrecht et al., 2000); improved C-reactive protein values (Church et al, 2002); and increased cytokine-activity (Goldhammer et al., 2005).It has been established that exercising at the HR of the VAT level has a favorable effect (Gordon & Scott, 1995).However, the means which exercise achieves this remains unclear.Does it enhance the development of collateral coronary blood supply to the ischemic myocardium?Or can the improvement in cardiopulmonary function be readily explained by other mechanisms such as a more "cost-effective" metabolic-physiologic demand-supply balance.According to the Fick formula (paragraph 2), O 2 -P, which is simply VO 2 divided by HR, is directly related to SV.If O 2 -P is significantly increased with exercise, it follows that exercise improves SV.Theoretically this could be induced by improved myocardial perfusion (e.g., augmented collateral circulation).However, until now there is a lack of evidence to show that exercise training indeed, exerts such a beneficial effect on myocardial oxygen supply.Alternatively, the increase in SV, especially if accompanied by a decrease in HR at VAT level, could simply reflect an improved and a more effective myocardial VO 2 as a result of exercising, which may be accompanied by an objective evidence of reduced myocardial ischemia.This could occur simply as a result of a significant decrease in HR during exercise.In this study, an assessment and comparison of the functional CPET indices in trained vs. untrained CAD patients was carried out.The CPET was followed by evaluation of the degree of ischemia in every patient by 99m TC sestamibi myocardial perfusion imaging (MIBI-SPECT), while using the same exercise testing for both studies.It was assumed that a decrease in myocardial oxygen demand could explain the improved functional capacity observed after exercise training in chronic CAD patients, irrespective of its possible effects on collateral blood flow.

Methods
44 men aged 40-83, a mean 62+/-12 years, with a recent coronary angiogram participated.They were divided into three age-coordinated groups: Group I, nine patients with normal coronary arteries at the coronary angiography (control group); Group II, 20 patients with significant 1-3 vessel disease who did not participate in any exercise training program (untrained group), and Group III, 15 patients also with significant 1-3 vessel disease, yet who completed a 3-6 month supervised, telemetry-monitored exercise training program prescribed by the HR at the VAT (trained group).All 35 CAD participants had chronic CAD, without any previous acute coronary events.All had normal LV function (LVEF>50%), documented by multigated acquisition angiography (MUGA) or LV angiography.All 44 participants underwent a CPET together with a MIBI-SPECT study using standardized techniques.A single exercise test was used for both studies.Beta-blockers and calcium channel antagonists were stopped 24 hours prior to testing.

CPET protocol
This test was performed as described in paragraph 2.1.1.

MIBI-SPECT protocol
MIBI myocardial perfusion tomography was performed with a same-day "rest-stress" imaging protocol (Tailefer, 1990).The first myocardial perfusion imaging was done at rest, one hour after the injection of MIBI 7-8 mc.The second imaging was done 1-2 hours later, after exercise and additional injection of MIBI 21-22 mc at peak-exercise.Tomographic imaging acquisition was performed over a 180-degree arc, from the -45-degree right anterior oblique to the +135-degree left posterior oblique with an S-P-4x digital camera (Elscint Ltd, Haifa, Israel) fitted with an all-purpose collimator.The degree of ischemia was scored on a 4-point scale as follows: 0-no ischemia; 1-mild; 2-moderate, and 3-severe ischemia.Only stress-imaging defects that showed partial or complete resolution on corresponding rest images were considered as "reversible ischemia".

Results
The basic data and summary of results for all three groups are shown in Table 8, and the extent of disease in the trained and untrained patients is shown in Table 9.There was an almost equal distribution of 1-, 2-and 3-vessel disease within groups II and III with no significant difference in the extent of disease between the groups (Table 9).Nevertheless, significantly less ischemia was observed in the trained patients (group III) in comparison to the untrained patients (group II) (0.8+0.65 vs. 1.79+0.95;p<0.001), as also demonstrated in Figure 3, along with a significantly greater peak-VO 2 (1989+422 vs. 1608+296 ml/min; p<0.001).Since peak-VO 2 equals peak-O 2 -P x HR, and a highly significant increase in peak-O 2 -P was observed in the trained vs. the untrained group (139+29% vs. 94+11% of predicted values; p<0.001) concomitantly with a significantly lower peak-HR (70+11% vs. 84+9% of predicted values; p<0.001), it indicates that the increase of peak-O 2 -P contributes more to the increase of peak-VO 2 than the reduction of peak-HR deletes from its level.The Peak-VO 2 and O 2 -P were not significantly different in the trained group (group III) vs. the control group (group I).The relationship between the peak-VO 2 , peak-O 2 -P and peak-HR within the three groups is demonstrated in Figure 4  Table 9. Extent of coronary disease on angiography in trained and untrained patients.

Exercise training in chronic and stable CAD
Exercise training is a highly valuable non-pharmacological treatment for patients with chronic stable angina.It reduces myocardial ischemia and, on the clinical level, reduces the frequency of anginal attacks while also improving functional capacity and long-term outcomes (Nigam & Tardif, 2008).As regular exercise has been shown to improve myocardial perfusion and to retard disease progression in patients with stable CAD and even with ischemic cardiomyopathy (Belardinelli et al., 1998), a randomized study was conducted (Hambrecht et al., 2004) to compare the effects of exercise versus percutaneous coronary intervention with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion and cost-effectiveness.It was concluded that a 12-month program of regular physical exercise in patients with stable CAD resulted in superior event-free survival and exercise capacity at a lower cost, due to reduced re-hospitalizations and repeated revascularizations.What is the contribution of our study?
What is not clear from previous studies is the dominant mechanism that underlies the cardiovascular improvement induced by an exercise program.Is the improvement mainly dominated by enhanced myocardial blood flow (by increased coronary collateralization for example, as well as by augmentation in endothelial function) or is it due to decreased myocardial oxygen demand and improved metabolic cost effect balance? (The improved ischemic burden evidenced by perfusion studies is compatible with either one of these possibilities).This study does not deny the former possibility of increased myocardial perfusion, since it does not address this issue.However, it does show that the reduced ischemic burden seen in perfusion studies can be attributed substantially, if not completely, to the improved metabolic-physiologic state of the myocardium that accrues from exercise training.It is shown here that SV (as indicated by O 2 -P) is significantly higher in the CAD patients after a 3-6 month training program (group III) than in group II patients, who were not subjected to training yet had similar severity of CAD, and also similar to SV levels of subjects without CAD (group I, control).Furthermore, peak-VO 2 is also significantly higher in the trained group than in the untrained one, indicating an improvement in functional capacity.Simultaneously, peak-HR is also significantly lower in the trained group at a higher degree of exercise, as expressed by higher peak VO 2 , than in the untrained group (Figure 4).This peak-HR decrease indicates that exercise training decreases myocardial oxygen demand, and the combination of this with the cardio-pulmonary data suggests that the beneficial effect of regular exercise is mediated, at least substantially, by a significant decrease in peak-HR along with the significant increase in peak-O 2 -P (related to SV) and peak-VO 2 (functional capacity).This metabolic-physiological advantage to the myocardium  Peak VO2 (ml/min) Peak O2-P (% pred)

Quantitative assessment of patients with varying degrees of coronary artery disease by cardiopulmonary exercise and recovery indices
Recovery indices of CPET are important tools for assessing the exercise capacity of patients with CHF, which differ significantly from healthy subjects, as shown in our former study (Klainman et al., 2004).The kinetics of post-exercise VO 2 is shown to be delayed in relationship to the severity of the disease and closely related to exercise capacity (Cerretelli et al., 1996;Hayashida et al., 1993;Sietsema et al., 1994).The ability to estimate quantitatively the severity of CAD by a non-invasive test, such as the CPET, might be of great value for directing further management of these patients.In this study we measured three recovery O 2 kinetic indices as detailed below, in order to compare patients with varying degrees of CAD.

Methods
62 ambulatory patients were selected in this study on the basis of the following criteria:  All patients were men to avoid gender physiological discrepances.


All patients have performed a coronary angiogram within two months prior or post a CPET (which been done in all patients as well).


All the CPETs were well qualified for collecting relevant data for the purpose of the study.


No patients with a history of pulmonary, valvular or peripheral vascular diseases, CHF, left ventricular dysfunction, or chronic atrial fibrillation were selected.


All patients stopped all relevant medications: beta-blockers, calcium channel antagonists and nitrates at least 24 hours prior to the CPET.17 patients who demonstrated a normal coronary angiogram were defined as the control group (group A).The other 45 patients had documented CAD based on stenosis of 60% and above, in at least one major coronary artery, excluding the left main or proximal LAD stenosis.On the basis of the coronary angiogram results, patients were divided into three additional groups: B, 26 patients with mono-artery disease (1VD); C, 11 patients with twovessel disease (2VD), and D, 8 patients with three-vessel disease (3VD).

CPET protocol
The exercise protocol was carried out as described in paragraph 2.1.1.Data were recorded during exercise and recovery periods until the respiratory exchange ratio (RER) of 1 or less was reached.Three recovery indices were defined as follows: 1) half-time recovery of VO 2 (1/2tRec-VO 2 ), which is the time, in seconds, of peak-VO 2 reaching half of its value.2) halftime recovery of oxygen pulse (1/2tRec-O 2 -P), which is the time, in seconds, of peak-O 2 -P reaching half of its value, and 3) total-time recovery of VO 2 (TtRec-VO 2 ), which is the time, in minutes, from peak exercise end-point till obtaining an RER value of 1 or less.

Statistical analysis
Data were analyzed by the SAS system, using the Duncan's Multiple Range Test to compare the variables of each group.Values were calculated as mean +/-1 standard deviation (SD).P values <0.05 were considered statistically significant.P values of 0.06-0.1 were considered as borderline.Values of > 0.1 were not significant.
Quantitative Functional Assessment of Ischemic Patients by Cardiopulmonary Exercise and Recovery Indices 75

Post-exercise recovery period
Few data are available in regard to VO 2 kinetics in recovery among patients with CAD.Traditionally, the rate of VO 2 recovery from exercise indicates the oxidative capacity in healthy subjects, and its decrease has been related to the oxygen debt following exercise (Barstow, 1987;Di Prampero, 1970).This oxygen debt has been considered to involve a first, fast alactatic phase and a second, slow lactatic component (Margaria et al., 1933).More recently, the term excess post-exercise oxygen consumption has been used to express more complex mechanisms which mediate the post-exercise VO 2 recovery, and absolve this entity from a total dependence on anaerobic metabolism (Gaesser, 1984).A relatively fast recovery time of oxygen consumption has been demonstrated in athletes (McCully et al., 1992), while a delay of oxygen kinetics is shown in heart failure patients.The later may involve a delay of several factors, such as circulatory transport of oxygen to and from metabolizing tissue (Koike et al., 1989), pulmonary gas exchange (Sullivan et al., 1988b), or oxygen consumption of the exercising/recovering muscles themselves.One important factor, which contributes to the delayed recovery of VO 2 , is the prolonged recovery of the muscle phosphate/phosphocreatine ratio, which is determined by the blood flow as well as by the oxidative capacity of the exercising muscles (Chati et al., 1994;Sapega et al., 1987;Wiener et al., 1986).Other central factors, which may explain the slower VO 2 recovery in patients with heart failure, are higher cardiac output and increased SV during the early recovery period (Koike et al., 1990), which are directly related to VO 2 and O 2 -P respectively, according to the Fick formula, as discussed previously.The arterio-venous oxygen difference, which appears in the formula, shows a rapid decline after exercise, thus supporting the direct relationship between the central factors to VO 2 and O 2 -P (Sumimoto et al., 1991(Sumimoto et al., , 1993)).Both healthy subjects and patients with CAD demonstrated elevated cardiac output and ejection fraction during early recovery (Plotnick et al., 1986), and the CAD patient levels were even higher.It is suggested that an existence of a transient mismatch between cardiac contractility and after-load reduction during recovery, even from mild-intensity exercise, in healthy subjects as well as in CAD patients, might be the mechanism of overshoot in cardiac function observed in the early-recovery phase (Kano et al., 1999).According to the above, we hypothesized that patients with CAD may also demonstrate similar changes in recovery indices since ischemic reaction during exercise might be considered as temporary LV dysfunction in correlation to the severity of the ischemic reaction.In our study, there are significant differences in the recovery VO 2 indices between the healthy group and the CAD groups, with a clear tendency of delayed recovery in parallel to the severity of the CAD.Our results demonstrate such differences, which are emphasized more in group D (3VD), where the sub-maximal exercise was mostly limited for the severity of the CAD.This supports other studies in which even mild-intensity or sub-maximal exercise was enough for showing slower recovery kinetics of VO 2 in CAD (Kano et al., 1999) and CHF patients (Cohen-Solal et al., 1995) compared to healthy subjects.Our findings do not concur with Pavia et al. which do not show significant differences between CAD and healthy subjects.In some patients the kinetics of VO 2 recovery may be complex and incorrectly described by a single exponential curve (Henry, 1951) as opposed to another later report (Hayashida et al., 1993).Thus, Cohen-Solal et al. characterized recovery kinetics by measuring the half-time of VO 2 recovery, while also measuring the time for RER to reach level 1 or less (Lim et al., 1998).In this study, the three recovery indices, mentioned above (paragraph 6.1.1)were measured.All three indices differ significantly among the four groups studied.The 1/2tRec-VO 2 Quantitative Functional Assessment of Ischemic Patients by Cardiopulmonary Exercise and Recovery Indices 77 shows a significant systematic progression of increased time from group A (control group) to group D, while the two other indices show only a tendency for such a progression.Moreover, these last two indices differ significantly between groups A or B vs. C or D. Group B appears closer to A while C appears closer to D, inferring that mono-artery disease should be considered for further conservative treatment rather than invasive procedures.Such significant differences were not demonstrated in most of the exercise indices (Table 1, lines 2-10).These findings validate the recovery indices as even more important than those in quantitative functional evaluation of varying degrees of CAD.

Conclusions
We have concluded that recovery cardiopulmonary indices of VO 2 kinetics are important in evaluating patients with CAD and may differ functionally according to the degree of disease.Thus, additional recovery measurement indices are recommended for the standard CPET in order to obtain a more comprehensive and quantitative assessment of the functional degree of CAD, which seems to correlate with the anatomical findings of the coronary angiogram.Additional studies are recommended to further establish these findings.

Clinical applications
The present study provides a simple, non-invasive physiological tool for evaluating the severity of ischemia in patients with CAD, following and in addition to the anatomical results of the coronary angiogram.Furthermore, this tool may be used for identifying patients with varying degrees of ischemia, prior to coronary angiogram and accordingly, indicate them for further treatment -conservative or invasive.

Summary
In the five studies reported in this chapter, we emphasize the important contribution of cardiopulmonary indices, during both exercise and recovery, for quantitative functional assessment of patients with CAD.The most important indices for measuring ischemic exercise responses were: Peak-VO 2 ; peak-O 2 -P; VAT; O 2 -P curve characteristics, all measured during exercise; and three relatively new indices, measured during the recovery period: total-time and half-time recovery kinetics of VO 2 , and half-time recovery of O 2 -P.Using these indices it was shown that it is possible to quantitatively assess the functional results following invasive procedures like PTCA in chronic CAD patients as well as exercise training results in similar patients.The results from these two groups support the assertion that benefits of regular exercise training are not inferior to the invasive procedure, at least in patients with one-or two-vessel CAD.Also illustrated here is a possible mechanism for better understanding the training effect in those patients.It is suggested that the increase in the O 2 -P, which reflects an increase in SV following exercise training program, causes a gradual decrease in exercise HR, while maintaining the same or an even higher VO 2 level during exercising.As a consequence, there is a decrease in myocardial oxygen demand.This metabolic-physiologic advantage to the myocardium is expressed by significant improvement of isc h e m i a a s d e m o n s t r a t e d b y M I B I -S P E C T imaging at peak-HR in trained patients compared to untrained ones.Finally, it has been shown how the recovery O 2 kinetic indices may contribute, in addition to the exercise indices, to quantitative comparison among varying degrees of CAD, as expressed during CPET.All indices mentioned above, further validate the CPET as an effective, noninvasive, and essential tool for quantitative functional assessment of CAD patients and, accordingly, may even provide an indication of further treatment required -conservative or invasive, in chronic and stable patients.

Fig. 1 .
Fig. 1.The four O 2 -P curve variables.Type A (top left): normal curve, 10 points; Type B (top right): normal curve, lower values, 8 points; Type C (bottom left): flat curve, low values, 5 points; Type D (bottom right): descending curve, 3 points.Dashed curve refers to O 2 -P response.Continuous curve refers to the HR response.The dash-dot horizontal line refers to predicted O 2 -P values.
shows the linear regression between these two factors, defined by the equation:Y = -2.1X+ 11.85Where Y represents O 2 -P-curve scoring and X represents MUGA grouping.
www.intechopen.comQuantitative Functional Assessment of Ischemic Patients by Cardiopulmonary Exercise and Recovery Indices 69 ETT = exercise treadmill time; max HR = maximal heart rate; max ST  = maximal ST segment depression; rec.time = time of recovery of ST changes; NS = non significant, statistically

Fig. 3 .
Fig. 3. Comparison of number of occluded coronary vessels and scoring of ischemic degree (Tecnetium-Sestamibi test) between groups II (untrained) and III (trained).

Table 1
. Relationship between MUGA grouping and O 2 -P-curve scoring

Table 2 .
Patient basic data and coronary angiography findings prior to PTCA (n=29).

Table 4 .
Summarized CPET results before and after successful PTCA (n=27)

Table 7 .
In groups 1 and 2, no significant changes occurred in the standard exercise variables; testing time, peak-HR, maximal ST segment depression and recovery time.Nevertheless, there were significant improvements in the cardiopulmonary indices; peak-VO 2 , peak-O 2 -P, O 2 -P curve levels, and VAT levels.By contrast, group 3 showed significant changes only in the O 2 -P curve, while group 4 (LV dysfunction), showed significant improvements in all cardiopulmonary indices except the standard exercise test variables (as did groups 1 and 2).

Table 6 .
Baseline variables and data from the exercise training program of the four groups

Table 7 .
CPET indices before and after the exercise training program in the four groups. www.intechopen.com .

Table 8 .
Basic data and summary of results.
Table10summarizes the group data of the CPET as mean +/-1 SD and shows the comparison of the exercise and recovery indices among the four groups.This table shows no significant differences of peak HR, % pred.HR, Ex. time and peak O 2 -P among the four groups (lines 2, 3, 4 and 7 respectively).A significant difference of peak-VO 2 was observed only between groups A and D, while borderline differences were shown between groups A vs. B; A vs. C; D vs. B; and D vs. C (line 5).Similar differences among the groups were observed in peak O 2 -P (% of predicted value) variable (line 8).Significant differences of peak VO 2 (% of predicted value) were observed between group D vs. A, B and C, but not among A, B and C themselves (line 6).Similar differences were shown in VAT variables (lines 9 and 10).Lines 2-10 summarize the exercise parameters, while lines 11-13 demonstrate the recovery indices.Significant differences of 1/2tRec-VO 2 were observed between the following groups: A vs. C; A vs. D; and B vs. D, while borderline differences were shown between groups: A vs. B; B vs. C; and C vs. D (line 11).Similar differences of the indices 1/2tRec-O 2 -P and TtRec-VO 2 were demonstrated among the groups (lines 12 and 13): Significant differences were apparent between A or B vs. C or D, but not between A vs. B or C vs. D.